The pathogenesis of the human immunodeficiency virus (HIV) is complicated and as of yet not completely understood. The virus life cycle has theoretically been divided into afferent and efferent components. Virus binding, fusion, reverse transcription, and finally integration are among those events which encompass the afferent component of the life cycle. It is the afferent component of the HIV life cycle which is responsible for primary infection of HIV in an individual, generally followed by a burst of viraemia with or without clinical symptoms.
In most individuals, a prolonged clinically asymptomatic period follows infection with the human immunodeficiency virus type 1 (HIV-1). During this period that normally spans 8 to 10 years, infected individuals remain in good health with adequate immune responsiveness. However, in the years that follow, the occurrence of opportunistic infections and the rapid devastation of immune responsiveness that characterizes AIDS eventually result in death. Therefore, the clinically asymptomatic period presents a therapeutic window of opportunity to prevent immune destruction if effective intervention can be implemented.
Key to the development of therapeutic intervention designed to prolong the asymptomatic period prior to AIDS is an understanding of the progressive events that ultimately result in immune destruction. While the influences controlling clinical progression to AIDS are certainly multifactorial, a critical facet is the continued replication of HIV-1 within target cells and tissues, especially the lymph nodes. In addition, there exist a large population of HIV-1 infected cells, in the peripheral circulation and the lymph nodes, that maintain the provirus in a clinically latent state. Based on currently available in vitro models of HIV-1 infection, when these latently infected cells encounter the proper extracellular stimuli, HIV-1 becomes replicationally active and produces progeny virions to further disseminate infection. Therefore, therapeutic intervention to alter clinical progression during the asymptomatic period must not only address the control of active HIV-1 replication, but also the inhibition of viral activation from microbiological latency.
An area that warrants further development is therapeutic targeting along cellular signaling pathways that result in HIV-1 transcriptional activation. Among the potential targets is nuclear factor-.kappa.B (NF-.kappa.B), a transcriptional enhancer important for HIV-1 activation. In resting cells, preformed NF-.kappa.B exists in the cytoplasm bound to its inhibitor I-.kappa.B. After immune or cytokine stimulation of the cell, NF-.kappa.B is released by phosphorylation, and proteolysis of I-.kappa.B, and translocates to the nucleus to activate transcription from promoters, including HIV-1, that contain a specific binding motif. Anti-oxidants and other pharmacologic agents that block HIV-1 promoter-directed gene expression may interfere with NF-.kappa.B activation or with other viral enhancers. Selective inhibition of cellular protein kinase C activity has also proven effective against HIV-1 expression. However, targeting of cellular signaling elements must retain some degree of viral specificity, otherwise these therapies may interfere with normal cellular and immune functions.
We have now discovered a series of benzothiophene, benzofuran and indole derivatives which are effective at inhibiting HIV-1 activation. Viral inhibition by these compounds resulted from a specific interference with HIV-1 transcription by targeting a cellular component other than NF-.kappa.B. Furthermore, these compounds returned cytokine-activated, HIV-expressing cells to a state of viral latency, even under conditions of continued viral stimulation, and prevented HIV-1 expression during chronic infection. The compounds also inhibit herpes virus, including herpes simplex I and II, and cytomegalovirus. Accordingly, these compounds are useful for treating and preventing cold sores, genital herpes, shingles, and cytomegalovirus retinitis.
An object of this invention is therefore to provide a method for inhibiting HIV or the activation of HIV in an HIV-infected individual, and a method for preventing and treating conditions caused by herpesviruses.